PROJECT SUMMARY/ABSTRACT: During human pregnancy, placental trophoblasts replace the smooth muscle, vascular endothelial (VE) cells, and elastic tissue of the walls of the uterine spiral arteries (SA) within the decidua basalis (DB), transforming these arteries into high-capacity vessels with distensible walls/enlarged lumens to promote blood flow to the intervillous space (IVS) and fetal development. A defect in uterine artery remodeling (UAR) underlies fetal growth restriction (FGR), preeclampsia (PE) and pre-term birth, which result in neonatal morbidity/mortality. Non-invasive real-time methods to detect impaired UAR in the first trimester would be highly advantageous to more effectively diagnose and treat PE, preterm birth and FGR. A major limitation of widely used Doppler is that it does not reliably detect impaired UAR earlier than the second trimester and is limited by ?blooming? artifacts, aliasing, and signal dropout. We have shown that elevating estradiol (E2) levels in early baboon pregnancy suppressed UAR and caused maternal VE dysfunction and FGR. Our baboon translational model provides a novel experimental paradigm in which to establish real-time imaging technologies to assess SA perfusion as an index of UAR. Contrast-enhanced ultrasonography (CEU)/microbubble (MB) imaging is used to assess blood flow diagnostically in men and nonpregnant women, but currently cannot be performed in pregnant women carrying to term. We propose that CEU/MB provides a real-time acoustic snapshot of the volume/lumenal area of and flow within the SA as structural and functional indices of UAR. Ultrasound B-flow is a 4D non-Doppler technology and we have for the first time superimposed M-mode on B-flow to quantify with exceptional spatial resolution SA diameter and mural distensibility. The overall goal of this study is to establish CEU/MB and B-flow/M-mode as novel prototypes to quantify SA volume/flow and diameter/distensibility, respectively, as complementary structural and functional indices of UAR across normal and abnormal pregnancy. Aim 1 will test the hypothesis that CEU/MB and B- flow/M-mode provide state-of-the-art approaches to quantify SA perfusion and diameter/distensibility, as indices of UAR, in baboons untreated or treated with E2 which suppresses UAR. Maternal, placental and fetal physiological parameters will be ascertained in baboons after CEU/MB to establish safety standards for the application of CEU/MB to human pregnancy. Aim 2 will test the hypothesis that ultrasound B-flow/M-mode provides a novel method to quantify SA diameter/distensibility, as structural and functional indices of UAR, across normal pregnancy and as an early marker of abnormal human pregnancy. Completion of this study is expected to establish innovative imaging methods that will lead to more effective prediction and management of adverse human pregnancy arising from defective UAR.